The molecular mechanisms underlying fatty liver progression towards more severe syndromes are complex and only partially understood. Studies have recently reported that lipotoxic fatty acid metabolites are instrumental in the development of hepatocyte injury in the context of fatty liver disease. The recent study by Papazyan et al. published in Cell Metabolism (2016;24(6):863-874) addresses this issue and reveals that rescuing de novo fatty acid synthesis (lipogenesis) through the activation of the transcription factor SREBP-1c can prevent lethality as well as severe lipotoxicity caused by a combined deficiency in lipogenesis and β-oxidation. Altogether, this study reveals that optimizing lipid signals generated by lipogenesis through SREBP-1c can help redirect fatty acids toward beneficial actions, by buffering lipotoxic lipid intermediates even in the setting of lipid overload.